Hair follicles cycle through expansion, regression and quiescence. To investigate the role of MCL‑1, a BCL‑2 family protein with anti‑apoptotic and apoptosis‑unrelated functions, we delete Mcl‑1 within the skin epithelium using constitutive and inducible systems. Constitutive Mcl‑1 deletion does not impair hair follicle organogenesis but leads to gradual hair loss and elimination of hair follicle stem cells. Acute Mcl‑1 deletion rapidly depletes activated hair follicle stem cells and completely blocks depilation‑induced hair regeneration in adult mice, while quiescent hair follicle stem cells remain unaffected. Single‑cell RNA‑seq profiling reveals the engagement of P53 and DNA mismatch repair signaling in hair follicle stem cells upon depilation‑induced activation. Trp53 deletion rescues hair regeneration defects caused by acute Mcl‑1 deletion, highlighting a critical interplay between P53 and MCL‑1 in balancing proliferation and death. The ERBB pathway plays a central role in sustaining the survival of adult activated hair follicle stem cells by promoting MCL‑1 protein expression. Remarkably, the loss of a single Bak allele, a pro‑apoptotic Bcl‑2 effector gene, rescues Mcl‑1 deletion‑induced defects in both hair follicles and mammary glands. These findings demonstrate the pivotal role of MCL‑1 in inhibiting proliferation stress‑induced apoptosis when quiescent stem cells activate to fuel tissue regeneration.

Hepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2. Pericentral Cyp2e1+ and periportal Gls2+ hepatocytes maintain their own lineage during adult homeostasis, while Cyp2e1+ hepatocytes fuel neonatal liver growth. The Gls2+ and Cyp2e1+ populations can rapidly regenerate one another when one of the populations is severely damaged. Midlobular Ccnd1+ hepatocytes are enriched in the Cyp2e1+ zone in adult liver but have limited contributions to regeneration upon partial hepatectomy and severe pericentral injury. Remarkably, Lgr5+ hepatocytes, a unique Cyp2e1+ subset, contribute significantly to liver replenishment upon periportal injuries. Our findings unravel that zonal hepatocytes mainly self-maintain during homeostasis but exhibit complex plasticity in repair upon injury.

RNA sequencing (RNA-seq) is a gold standard technology for studying gene and transcript expression. Different transcripts from the same gene are usually determined by varying combinations of exons within the gene, formed by splicing events. One method of studying differential alternative splicing between groups in short-read RNA-seq experiments is through differential exon usage (DEU) analysis, which uses exon-level read counts along with downstream statistical testing strategies. However, the standard exon counting method does not consider exon-junction information, which may reduce the statistical power in detecting splicing alterations. We present a new workflow for differential splicing analysis, called differential exon-junction usage (DEJU). This DEJU analysis workflow adopts a new feature quantification approach that jointly summarises exon and exon–exon junction reads, which are then integrated into the established Rsubread-edgeR/limma frameworks. We performed comprehensive simulation studies to benchmark the performance of DEJU against existing methods. We also applied DEJU to a mouse mammary gland RNA-seq dataset, revealing biologically meaningful splicing events that could not be detected previously. We demonstrate that incorporating exon–exon junction reads significantly improves the detection of differential splicing events. The proposed DEJU workflow offers increased statistical power and computational efficiency compared to widely used existing approaches, while effectively controlling the false discovery rate.

Fibroblasts form a major component of the stroma in normal mammary tissue and breast tumors. Here, we have applied longitudinal single-cell transcriptome profiling of >45,000 fibroblasts in the mouse mammary gland across five different developmental stages and during oncogenesis. In the normal gland, diverse stromal populations were resolved, including lobular-like fibroblasts, committed preadipocytes and adipogenesis-regulatory, as well as cycling fibroblasts in puberty and pregnancy. These specialized cell types appear to emerge from CD34high mesenchymal progenitor cells, accompanied by elevated Hedgehog signaling. During late tumorigenesis, heterogeneous cancer-associated fibroblasts (CAFs) were identified in mouse models of breast cancer, including a population of CD34- myofibroblastic CAFs (myCAFs) that were transcriptionally and phenotypically similar to senescent CAFs. Moreover, Wnt9a was demonstrated to be a regulator of senescence in CD34- myCAFs. These findings reflect a diverse and hierarchically organized stromal compartment in the normal mammary gland that provides a framework to better understand fibroblasts in normal and cancerous states.

Hair follicles (HFs) cycle between expansion, regression and quiescence. To investigate the role of MCL-1, a BCL-2 family protein with anti-apoptotic and apoptosis-unrelated functions in this dynamic process, we deleted Mcl-1 within the skin epithelium using both constitutive and inducible systems. Constitutive deletion of Mcl-1 did not impair HF organogenesis but resulted in gradual hair loss and elimination of HF stem cells (HFSC) while acute Mcl-1 deletion rapidly depleted activated HFSCs in adult mice. Single-cell RNA-seq profiling revealed that HFSCs are under proliferation-associated stress during depilation-induced anagen. The ERBB pathway was shown to play a central function in conferring the survival of adult activated HFSCs through promoting MCL-1 protein expression. Remarkably, the loss of a single Bak allele rescued Mcl-1 deletion-induced defects in HFs. These findings demonstrate the pivotal role of MCL-1 in inhibiting stress-induced apoptosis when quiescent stem cells undergo activation to fuel tissue regeneration. Hui San Chin, Jinming Cheng, Shih Han Hsu, Guo Guang Lum, Maria TK Zaldiva, Fusheng Guo, Keerthana Mallavarapu, Felicity C. Jackling, Gordon K. Smyth, Geoffrey J. Lindeman, Andreas Strasser, Jane E. Visvader, Yunshun Chen, Ting Chen, Nai Yang Fu. MCL-1 safeguards activated hair follicle stem cells to enable adult hair regeneration [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P51.

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC, which is abnormally highly expressed in ~70% of human cancers, we use a genome-wide CRISPR gene knockout screen in Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discover that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerates c-MYC-driven lymphoma development in mice. MYC-driven lymphomas lacking GATOR1 display constitutive mTOR pathway activation and are highly sensitive to mTOR inhibitors, both in vitro and in vivo. These findings identify GATOR1 suppression of mTORC1 as a tumor suppressive mechanism in MYC-driven lymphomagenesis and suggest an avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition.

Parity and breastfeeding reduce the risk of breast cancer, particularly triple-negative breast cancer (TNBC)1,2, yet the immunological mechanisms underlying this protection remain unclear. Here we show that parity is associated with increased numbers of CD8+ T cells, including cells with a tissue-resident-memory-like phenotype within human normal breast tissue. In mouse models, pregnancy followed by lactation and involution drove the accumulation of CD8+ T cells in the mammary gland, coinciding with reduced tumour growth and increased intratumoural immune cell infiltration, effects that were abrogated by CD8+ T cell depletion. Importantly, this CD8+ T-cell-dependent tumour control was observed only after a complete cycle of lactation and involution. Consistent with this, primary triple-negative breast cancers from parous women exhibited greater T cell infiltration and improved clinical outcomes. Together, these findings, spanning preclinical models and over 1,000 patient samples, provide insights into how reproductive history shapes breast immunity, positioning CD8+ T cells as key mediators of parity-associated protection and informing strategies for both the prevention and the treatment of breast cancer.

A deeper understanding of the complicated transcriptional landscape of human breast cancers are vital to identifying more efficacious treatments. Investigating genetic variations among breast cancer subtypes at a single-cell level holds the potential to enhance our understanding of cancer formation, progression, and elucidate actionable targets. In this study, we compile single-cell RNA sequencing data from patient tumors and matched lymph metastasis, reduction mammoplasties, breast cancer patient-derived xenografts (PDXs), PDX-derived organoids (PDXOs), and cell lines, forming a diverse dataset consisting of 117 samples with a total of 506,719 cells. These samples include hormone receptor-positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), and triple-negative breast cancer (TNBC) subtypes, along with isogenic model pairs. Within this study, we outline the similarities and differences across these models and patient samples, and assess therapeutic drug efficacy based on subtype proportions. Within the TNBC subtype, PDX models exhibited a closer resemblance to patient samples in terms of tumor heterogeneity and cell cycle features compared to cell lines. Acquired drug resistance in TNBC PDX tumors was linked to an increase in basal-like cell proportions, as defined by SCSubtype and TNBCtype cell typing predictors. Cell-wise subtyping revealed all patient samples comprised a mix of subtypes; notably, HR+ lymph node metastases had a lower proportion of HER2-Enriched cells compared to matched primary tumors. PDXOs displayed differences in metabolic-related transcripts relative to matched PDX tumors. Correlative analyses of cytotoxic drugs on PDX cells demonstrated that therapeutic efficacy was dependent on subtype proportions. Herein we provide an extensive multi-model dataset, a dynamic approach to cell-wise sample annotation, and a thorough examination of models within human breast cancer systems. This analysis and reference resource will support informed decision-making in preclinical research and therapeutic development by establishing model limitations, subtype-specific insights, and novel targetable pathways. Citation Format: Julia Altman, Amy L. Olex, Emily K. Zboril, Carson J. Walker, David C. Boyd, Rachel K. Myrick, Nicole S. Hairr, Jennifer E. Koblinski, Madhavi Puchalapalli, Bin Hu, Mikhail G. Dozmorov, X. Steven Chen, Yunshun Chen, Charles M. Perou, Brian D. Lehmann, Jane E. Visvader, J. Chuck Harrell. Single-cell transcriptional features of human breast tumors and model systems [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-06-19.

Background: CDK4/6 inhibitors induce growth arrest/senescence in breast cancer cells, which become refractory to apoptotic cell death. In preclinical models, the BCL2 inhibitor venetoclax augmented tumor response to endocrine and CDK4/6 inhibitor therapy, by triggering apoptosis. This is now being tested in PALVEN, a phase 1b dose escalation study in patients (pts) with ER+ and BCL2+ metastatic breast cancer (MBC). The maximum tolerated and recommended phase 2 dose has been defined as letrozole 2.5 mg (d1-28), palbociclib 75 mg (d1-21) and venetoclax 400 mg (d1-21). Here, we present the clinical benefit rate (CBR) and response rate (RR) at 24 wks and report treatment-related toxicity. Methods: Participants included post-menopausal women with ER+/HER2– (ASCO/CAP) and BCL2+ MBC who had received ≤2 prior lines of systemic therapy in the metastatic setting. Patients (pts) with evaluable disease were included. Tumor assessment occurred every 8 wks. Secondary endpoints included CBR and RR defined by RECIST v1.1 within the first 24 wks of treatment. Adverse events from venetoclax, palbociclib and letrozole were reported using the CTCAE v5.0 grading system. Results: As of 19 June 2024, sixteen pts had received venetoclax, palbociclib and letrozole treatment and fifteen were DLT-evaluable (median age 50 yrs [range 36-67]), with a median follow-up time of 29.2 months. Of the DLT-evaluable population, 8 pts had de novo MBC and 7 pts had relapsed MBC, with 9 pts having previously received endocrine therapy in either the adjuvant or metastatic setting. Three pts had received prior systemic treatment for MBC; 1st line aromatase inhibitor therapy (2 pts), chemotherapy followed by tamoxifen (1 pt). At the 24-wk tumor assessment, 60% (9/15) of patients had achieved a partial response (PR), 33% (5/15) had stable disease (SD), and one pt had progressive disease. The CBR (rate of confirmed complete response or PR or SD ≥24 wks) was 93% (14/15 pts). Of thirteen pts with baseline measurable disease, 9 (69%) achieved a PR by 24 wks. In pts who were previously untreated in the metastatic setting, the CBR was 100% (12/12), 89% (8/9) for pts who had previously received endocrine therapy in the adjuvant or metastatic setting. For pts with strong (IHC 3+) BCL2 expression, CBR was 88% (7/8). An interim safety analysis of all eligible pts that received at least one dose of triple therapy (n=16), determined the most common non-hematological treatment-related adverse events (TRAEs) of any grade were fatigue (75%), nausea (69%), arthralgia (50%), hot flashes (44%), constipation (44%) and diarrhea (44%). Grade ≥3 hematological TRAEs were decreased neutrophil count (63%), reduced white cell count (44%) and decreased lymphocyte count (19%). There were no AEs of special interest since dose level 1 (G3/4 AST/ALT elevations in 2 pts). No treatment-related deaths were reported. Two pts ceased triple therapy due to intolerable TRAE, including one with arthralgia attributed to letrozole alone. Conclusion: Triple therapy with palbociclib, letrozole and venetoclax in ER+ and BCL2+ MBC is well tolerated and shows promising clinical activity in pts with endocrine sensitive and CDK4/6 inhibitor-naive disease. Our findings suggest that combining a BCL2 and CDK4/6 inhibitor in endocrine responsive breast cancer merits further investigation. (IIS funded by NHMRC, NBCF, Cancer Australia, BCRF, BCT, VCCC, with support from AbbVie & Pfizer; NCT03900884). Citation Format: Geoffrey Lindeman, Christine Muttiah, Felicity C Martin, Michael Christie, Sarah-Jane Dawson, Jayesh Desai, Luxi Lal, Kate Moodie, Anand Murugasu, Phuong Phan, Mark R Rosenthal, Avraham Travers, Jane E Visvader, James R Whittle, Belinda Yeo. Results from PALVEN: A Phase 1b Study of Palbociclib, Letrozole and Venetoclax in ER and BCL2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-18.

Supplementary Figure S18 showing that removal of mutant TP53 in SUM159 human breast cancer cells does not impair metastasis in vivo

Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2mut/+ tissue, including expansion of aberrant ERBB3lo luminal progenitor and mature cells, and the presence of atypical oestrogen receptor (ER)-positive lesions. Transcriptional profiling and functional assays revealed perturbed proteostasis and translation in ERBB3lo progenitors in BRCA2mut/+ breast tissue, independent of ageing. Similar molecular perturbations marked tumours bearing BRCA2-truncating mutations. ERBB3lo progenitors could generate both ER+ and ER- cells, potentially serving as cells-of-origin for ER-positive or triple-negative cancers. Short-term treatment with an mTORC1 inhibitor substantially curtailed tumorigenesis in a preclinical model of BRCA2-deficient breast cancer, thus uncovering a potential prevention strategy for BRCA2 mutation carriers.

AbstractBackgroundBreast cancer's complex transcriptional landscape requires an improved understanding of cellular diversity to identify effective treatments. The study of genetic variations among breast cancer subtypes at single‐cell resolution has potential to deepen our insights into cancer progression.MethodsIn this study, we amalgamate single‐cell RNA sequencing data from patient tumours and matched lymph metastasis, reduction mammoplasties, breast cancer patient‐derived xenografts (PDXs), PDX‐derived organoids (PDXOs), and cell lines resulting in a diverse dataset of 117 samples with 506 719 total cells. These samples encompass hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), and triple‐negative breast cancer (TNBC) subtypes, including isogenic model pairs. Herein, we delineated similarities and distinctions across models and patient samples and explore therapeutic drug efficacy based on subtype proportions.ResultsPDX models more closely resemble patient samples in terms of tumour heterogeneity and cell cycle characteristics when compared with TNBC cell lines. Acquired drug resistance was associated with an increase in basal‐like cell proportions within TNBC PDX tumours as defined with SCSubtype and TNBCtype cell typing predictors. All patient samples contained a mixture of subtypes; compared to primary tumours HR+ lymph node metastases had lower proportions of HER2‐Enriched cells. PDXOs exhibited differences in metabolic‐related transcripts compared to PDX tumours. Correlative analyses of cytotoxic drugs on PDX cells identified therapeutic efficacy was based on subtype proportion.ConclusionsWe present a substantial multimodel dataset, a dynamic approach to cell‐wise sample annotation, and a comprehensive interrogation of models within systems of human breast cancer. This analysis and reference will facilitate informed decision‐making in preclinical research and therapeutic development through its elucidation of model limitations, subtype‐specific insights and novel targetable pathways.Key points Patient‐derived xenografts models more closely resemble patient samples in tumour heterogeneity and cell cycle characteristics when compared with cell lines. 3D organoid models exhibit differences in metabolic profiles compared to their in vivo counterparts. A valuable multimodel reference dataset that can be useful in elucidating model differences and novel targetable pathways.

Abstract Breast cancer's complex transcriptional landscape requires a deep understanding of sample and cell diversity to identify effective treatments. In this study, we amalgamate single-cell RNA sequencing data from breast cancer patient-derived xenografts (PDX), organoids, cell lines, patient tumors and reduction mammoplasties resulting in a comprehensive dataset of 117 samples with 506,719 total cells. These samples encompass hormone receptor positive (HR+), human epidermal growth factor receptor 2 enriched (HER2E), and triple-negative breast cancer (TNBC) subtypes. We aimed to delineate similarities and distinctions across model systems and patient samples while also exploring stratification of therapeutic drug efficacy based on subtype proportions within tumors. Mammary tumor PDXs, organoids, and established cell lines exhibited higher proliferation and lower heterogeneity observed via UMAP dimensionality reduction compared to most patient tumors or normal breast epithelium. TNBCs had elevated proliferative and pro-metastatic signatures compared to HR+ and HER2E samples. Interestingly, compared to matched PDX tumors, organoids from these same models were found to exhibit stark differences in gene expression, including upregulation of metabolically active aldo-keto reductase family genes, highlighting differences in the model systems with implications for pre-clinical drug testing. Single-cell tumor subtyping analyses with scSubtype and TNBCtype methods found that therapeutically treated samples had shifts in the proportions of cell-wise subtype annotations when compared to matched untreated samples. Similarly, patient lymph node metastasis when compared with matched primary tumors were significantly linked to decreases in Basal-like and HER2-enriched cell-wise annotations in untreated ER+ samples. In vitro assessment of anti-cancer compounds on PDX cells showed significant correlation of subtype proportion with cell viability following treatment with targeted therapeutic agents. This subtyping methodology offers a powerful tool to monitor the evolving gene expression landscape within samples and predict responses to therapeutic agents. We present here a dynamic approach to cell-wise sample annotation and a substantial multi-model dataset for use facilitating informed decision-making in preclinical research and therapeutic development. Citation Format: Julia E. Altman, Carson J. Walker, Emily K. Zboril, Nicole S. Hairr, Rachel K. Myrick, David C. Boyd, Jennifer E. Koblenski, Madhavi Puchalapalli, Bin Hu, Mikhail G. Dozmorov, Xi Chen, Yunshun Chen, Charles M. Perou, Brian D. Lehmann, Jane E. Visvader, Amy L. Olex, J. Chuck Harrell. Decoding breast cancer: Unraveling subtype and model differences through multi-model single-cell RNA sequencing data integration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1750.

Supplementary Figure S7 showing that complete removal of mutant TP53 in MDA-MB-231 cells does not impair survival and proliferation in culture

Abstract Combined CDK4/6 inhibitor and endocrine therapy has rapidly become standard therapy for patients with early line relapsed estrogen receptor (ER)-positive, HER2-negative breast cancer. Although this combination has been shown to significantly improve progression free and overall survival, relapse is virtually inevitable. This may in part be due to the profound cytostatic effect of CDK4/6 inhibitors on tumors, which is associated with reduced apoptotic cell death. It seems likely that growth arrested and/or senescent tumor cells acquire resistance to therapy, leading to relapse. BH3 mimetics are an emerging class of drug that target pro-survival proteins such as BCL2, BCL-xL and MCL1. Venetoclax, a BH3 mimetic that has potent and specific activity against BCL2, has shown considerable promise in hematopoietic tumors such as CLL, but has yet to be fully explored in solid tumors. We have previously demonstrated safety and efficacy of combining tamoxifen with venetoclax for patients with metastatic ER-positive BCL2-positive disease using pre-clinical PDX models and a dose-finding phase 1 study [mBEP study, ISRCTN98335443], where most patients were CDK4/6 inhibitor therapy-naïve. In the post-CDK4/6 inhibitor setting, however, venetoclax did not improve clinical benefit rate or progression free survival when added to fulvestrant in the phase 2 study VERONICA [NCT03584009]. In that study a minority of tumours exhibited strong BCL2 expression and exploratory biomarker analysis revealed a trend towards improved progression free survival for patients with tumors exhibiting high BCL2 expression (IHC 3+), a BCL2:BCL-xL Histoscore ratio ≥1, or with PIK3CA wild-type status. Using pre-clinical models including patient derived xenografts of ER-positive breast cancer, we have shown that the addition of venetoclax to dual therapy comprising fulvestrant and the CDK4/6 inhibitor palbociclib elicits a superior and more durable tumor response, accompanied by increased apoptosis. These findings have formed the basis of a phase 1 clinical trial of palbociclib, letrozole and venetoclax [PALVEN, NCT03900884] in patients with early line relapsed ER and BCL2-positive metastatic breast cancer. In parallel, pre-clinical studies are underway to determine the effect of dual targeting BCL-xL and MCL1, as well as dual targeting of AKT and with a BH3 mimetic in CDK4/6 inhibitor refractory breast cancer cells. Citation Format: James R Whittle, François Vaillant, Elliot Surgenor, Luuk Heitink, Christine Muttiah, Jane E Visvader, Geoffrey J Lindeman. Exploring breast cancer vulnerabilities through apoptotic pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA26.

Breast cancer kills hundreds of thousands of people every year. Rapid progress over the past two decades has increased our understanding of the genetic and environmental risk factors for disease. It has also shed light on drivers of tumor progression and the molecular landscape underpinning tumor heterogeneity, as well as the role of the microenvironment and the immune system. These strides forward should lead to more effective and tailored therapies for early- and late-stage patients.

Hormone-receptor-positive (HR+) luminal cells largely mediate the response to estrogen and progesterone during mammary gland morphogenesis. However, there remains a lack of consensus on the precise nature of the precursor cells that maintain this essential HR+ lineage. Here we refine the identification of HR+ progenitors and demonstrate their unique regenerative capacity compared to mature HR+ cells. HR+ progenitors proliferate but do not expand, suggesting rapid differentiation. Subcellular resolution, 3D intravital microscopy was performed on terminal end buds (TEBs) during puberty to dissect the contribution of each luminal lineage. Surprisingly, HR+ TEB progenitors were highly elongated and motile compared to columnar HR- progenitors and static, conoid HR+ cells within ducts. This dynamic behavior was also observed in response to hormones. Development of an AI model for motility dynamics analysis highlighted stark behavioral changes in HR+ progenitors as they transitioned to mature cells. This work provides valuable insights into how progenitor behavior contributes to mammary morphogenesis.

Supplementary Table S7 showing the impact of removal of mutant BRAF in human cancer cell lines in vitro by RNAi by mining the DepMap database