Highlighted Research Articles

Cancers evolve and are therefore subject to evolutionary forces. Cross, Nowinski, Cresswell, Mossner, Banerjee, Lu, and colleagues found evidence that negative selection could be limiting the ability of colorectal cancers to vary their chromosome makeup. Longitudinal analysis of genetic heterogeneity in samples from over 160 patients with colorectal-derived neoplasias across different stages and treatment suggested that, through the evolutionary pressures of negative selection, the genetic makeup of cancer cells is kept “stable” through long periods of time. Thus, this process of negative selection may represent a vulnerability for malignancies that, despite high genomic instability, cannot go too far “astray.”See article, p. 218.Resistance to antibody-drug conjugates (ADC) is poorly understood. Using preclinical models and analyses of paired biopsies, Chen and colleagues demonstrated that resistance to trastuzumab deruxtecan could occur via HER2 downregulation, HER2 loss, and, rarely, mutations in the trastuzumab binding site. This target-mediated resistance resulted in impaired ADC internalization and reduced payload delivery to cancer cells. Low-dose multi-target ADC combinations represent a promising strategy to overcome this mechanism of resistance, restoring payload delivery via alternative entry-points for drug internalization.See article, p. 235.Gumpert, Sagie, and colleagues uncovered recurrent immunogenic neoantigens and their cognate T-cell receptors (TCR) in treatment-resistant metastatic prostate cancer, through integrated HLA-immunopeptidomics, genomic profiling, and TCR sequencing. Recurrent neoantigens were derived from the ARH875Y mutation and mapped to their corresponding TCRs. Functional assays demonstrated that these TCRs selectively recognized and eliminated tumor cells presenting ARH875Y -derived neopeptides, revealing new therapeutic avenues for TCR-based immunotherapy in advanced prostate cancer. This work maps shared, targetable neoantigen responses across resistant tumors and establishes a foundation for precision immunotherapies addressing recurrent antigenic drivers.See article, p. 250.Why only some patients with metastatic colorectal cancer benefit from FOLFIRI remains unclear. Using patient-derived xenografts, tumoroids, and clinical samples, Avolio, Leto, and colleagues showed that chemosensitivity reflects a functional state of “BRCAness” rather than permanent inactivation of DNA repair genes. Drug-sensitive tumors exhibit low levels of the RAD51 recombinase, resulting in homologous recombination deficiency, characteristic genomic scars, and increased DNA damage. Modulating RAD51 expression or inhibiting the homologous recombination regulator ATM altered treatment response, and RAD51 status predicted clinical outcomes. These findings identify actionable biomarkers and therapeutic vulnerabilities that may refine patient stratification and expand options for chemorefractory disease.See article, p. 270.Osteosarcoma is a genomically complex malignancy with few targetable therapeutic vulnerabilities. Hypothesizing that osteosarcoma may be better defined by epigenetic subtypes, López-Fuentes and colleagues found evidence of two epigenetically distinct osteosarcoma cell states that mirror early and late osteoblast differentiation. These states were governed by distinct chromatin accessibility patterns, super-enhancer landscapes, and core regulatory transcriptional circuits, coexisted within individual tumors, and exhibited dynamic interconversion. Integrative bulk and single-cell multiomic analyses revealed that these epigenetic states were clinically detectable, prognostic, and differentially sensitive to targeted therapies. Simultaneous targeting of both states produced superior therapeutic responses in vivo. Together, this work establishes epigenetic cell identity as a key determinant of osteosarcoma biology and a rational framework for combination therapy in genomically complex cancers.See article, p. 296.Metastatic colorectal cancer displays pronounced transcriptional plasticity between an EMP1+ poor prognosis–associated state and an LGR5+ intestinal cancer stem cell state. Using the covalent KRASG12D RAS(ON) inhibitor RMC-9945, Centonze and colleagues showed that KRAS signaling sustains EMP1+ malignancy while suppressing the WNT-driven LGR5+ program. KRAS blockade rapidly reprogrammed metastases from EMP1+ to LGR5+ cells via a switch in transcription factor usage from AP-1 (JUN/FOS) to TCF/LEF with limited chromatin remodeling, enabling drug tolerance and progression. Eliminating LGR5+ cells after KRAS inhibition markedly reduces liver metastases and prolongs survival.See article, p. 320.Glucocorticoids (GC), widely considered immunosuppressive, are commonly used in the treatment of patients with cancer, including for the management of immunotherapy-induced side effects. Earnshaw and colleagues uncovered an unexpected cytotoxic T lymphocyte (CTL)-dependent antitumor effect of GCs in melanoma and other cancer models. GCs were shown to act directly on cancer cells to reduce GARP expression, leading to decreased TGFβ activity and enhanced CTL-mediated killing. In patients with melanoma, elevated GARP expression is associated with worse overall survival and impaired intratumoral CTL function. This work reveals a counterintuitive role for glucocorticoids in promoting antitumor immune control through cancer cell–intrinsic reduction of GARP expression.See article, p. 345.Glioblastoma cells form neural-like networks through tumor microtubes (TM) that drive invasion and therapy resistance. Azorín, Hoffmann, and colleagues developed a machine learning–guided screening platform to quantify TM structure and function across 2D cultures, human brain spheroids, and 3D in vivo models. A screen of 71 compounds identified protein kinase C (PKC) modulators as potent TM inhibitors. These agents disrupted tumor networks, silenced network calcium activity, and thereby sensitized tumors to radiotherapy. In mouse models, combining the PKC activator TPPB with radiotherapy reduced tumor burden and extended survival. Mechanistically, PKC modulation suppressed TTYH1, a key driver of TM invasion, establishing tumor network disconnection as a therapeutic strategy.See article, p. 367.Despite decades of research, cancer therapies targeting the p53 pathway remain elusive, underscoring the need for improved therapeutic design by better understanding mechanisms of p53-mediated tumor regression. Leveraging a p53 “super tumor suppressor”, Wang and colleagues deconstructed p53-driven transcriptional programs and sequelae underlying p53 therapeutic responses in lung adenocarcinoma (LUAD). p53 inhibits mTORC1, triggering autophagy/lysosome gene expression programs, senescence, and macrophage recruitment, culminating in tumor cell phagocytosis and tumor regression. Defining the cascade of events underlying a p53 therapeutic response in LUAD reveals targetable nodes for combination therapies with p53 activators, to enhance therapeutic efficacy while preempting toxicities and therapeutic resistance.See article, p. 391.