In this Voices piece, we asked researchers to reflect on how the Hallmarks of Cancer have shaped their career paths, their research directions, and their broader perspectives on cancer. Their reflections show how the framework continues to guide discovery, encourage collaboration across disciplines, and inspire new ways to better understand and treat cancer.

The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc–Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies. Blander and colleagues report a homeostatic regulatory effect played by inflammasomes in the bone marrow stromal compartment that suppresses premalignant stages of lymphomagenesis.

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.

Background: Triptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer cell compartments. In the epithelial tumour compartment, triptolide down-regulates key transcription factors such as c-MYC. Preclinical investigations indicate significant activity against super enhancer targets. In the phase I clinical trial of Minnelide™ activity in highly refractory metastatic pancreatic carcinoma was observed. Hence, we undertook this study in patients with chemotherapy refractory metastatic PDAC. Our aims were to determine clinical anticancer effects, and to define effects of the drug on super enhancer expression and downstream effects. Methods: Eligibility criteria included stage IV PDAC progressing on standard chemotherapy, Karnofsky performance status ≥ 70%, and measurable disease by RECIST 1.1. Planned sample size was up to 35 patients with interim analysis after the first 18 evaluable patients, aiming for at least a 20% difference in DCR (10% v 30%). Minnelide™ 0.67 mg/m2 was administered intravenously over 30 minutes on days 1-21, followed by a 7-day rest period in a 28-day cycle. Exploratory objectives included: analyses of paired tumour biopsies for changes in immune cell infiltration, stromal activation, chromatin accessibility, proteomics and metabolism. Results: 17 patients were treated. There were no RECIST responses or stable disease. However, evidence of activity was observed in 4 of 15 evaluable patients. This activity included progression after 117 days treatment in 1 patient and reductions in CT tumour size or FDG-PET uptake and/or significant decreases in circulating CA19.9 levels in 3 others. Minnelide was generally well tolerated. Treatment related toxicities > 3 were: neutropenia 4 patients and cerebellar ataxia 1 patient.Exploratory analyses included ATAC-Seq on paired biopsies where gene ontology analyses showed downregulation of genes negatively regulating cell cycle and upregulation of genes controlling cell cycle checkpoints. Other exploratory analyses will be presented. Conclusions: The study identified a tolerable drug dose and evidence of activity in a highly chemotherapy-refractory population which provides encouraging proof for the principle of targeting TFIIH in human PDAC. Supported by SU2C, Cancer Research UK, Lustgarten Foundation Citation Format: David Propper, Erkut Borazanci, Peter J. O'Dwyer, Daniel Von Hoff, Joseph Hartlebury, Corina E. Antal, Gerard I. Evan, HaiYong Han, Michael Downes, Ronald Evans, Joshua Rabinowitz, Emmanuel Petricoin, Ashok Saluja, Mohana Velagapudi, Hitendra Patel. Phase II open label trial of Minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT218.

Myc activation reversibly induces acinar-to-ductal metaplasia (ADM) in KMp48 pancreata in vivo and in isolated KMpdx1 pancreas cancer cells in vitro

tet-MycWT and tet-MycVD overexpression induces liver tumorigenesis.

Myc de-activation triggers regression of KMp48 pancreatic tumors

<p>Gene Lists</p>

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy 1 . The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study 2 . A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.

Clustering of MALDI imaging dataset for a lung section.

Ibrutinib does not affect growth of pancreatic cancer cell lines.

Gene ontology analyses of Myc-dependent and -independent DEG categories.

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Analyses and characterization of Myc-dependent and Myc-independent differentially expressed genes.

Tibial malunion and nonunion are complications that may follow the repair of traumatic tibial shaft fractures. Management may sometime require osteotomy and bone transport. In recent years, there has been a paradigm shift in the management of intercalary tibial defects away from bone transport via external fixation towards intramedullary lengthening nails. This shift necessitates a re-evaluation of the approach to infection and soft tissue defects.We describe the case of a young man with a two-year history of infected tibial nonunion who underwent osteotomy and debridement before requiring free tissue transfer and eventual bone transport. Second, we present the case of a middle-aged man with a 30-year history of infected tibial malunion. Prior to placement of the intramedullary nail, debridement and osteotomy were performed, followed by two free anterolateral thigh flaps and tissue rearrangement.The use of free tissue transfers and emphasis on achieving an anatomically correct lower extremity prior to the initiation of bone transport resulted in minimal external fixation time, treatment compliance, and satisfactory clinical outcomes. Although multiple treatments can produce successful bone transport, no cohesive treatment algorithm exists that addresses infection, external fixation time, healing, and psychological burden.The paradigm shift towards intramedullary bone transport devices requires the use of antibiotic implants and prioritization of the soft tissue envelope prior to device implantation to prevent hardware infection and reoperation. An algorithmic management approach by an orthoplastic surgical team that includes an orthopedic surgeon and microsurgeon is recommended.

Myc instructs immediate onset of transition to pancreatic adenocarcinoma in KMpdx1 mice

Staining for proliferation and apoptosis before and after MYC deactivation.

Example chromatograms for eicosanoid analysis by LC-MS/MS.

Supplementary Methods PDF file - 98K, Supplementary materials and methods