Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations^1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants³. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS⁴. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Acinar transdifferentiation toward a duct‐like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation‐induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar‐to‐ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation‐induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar‐to‐ductal conversion and PDAC initiation through direct transcriptional induction of Sox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.

Pancreatic ductal adenocarcinoma is a deadly disease and is projected to become the second leading cause of cancer-related death by 2030. A major hallmark is the exuberant host response comprising the tumor microenvironment, of which, cancer-associated fibroblasts (CAF) are a prevalent component. Despite the gains in understanding of their heterogeneity and functionality from CAF studies in recent years, there are many unanswered questions surrounding this diverse population of cells. Here, we summarize the views of several experts in the field, focusing on the current understanding of CAFs and challenges to address.

The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.Significance: We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment.This article is featured in Selected Articles from This Issue, p. 201

Given its aggressive tumor biology and its exceptional therapy resistance, pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <8%. At the cellular level, PDAC is largely driven by the activation of signaling pathways that eventually converge in altered, tumor-promoting transcription programs. In this study, we sought to determine the interplay between transforming growth factor β (TGFβ) signaling and activation of the inflammatory transcription factor nuclear factor of activated T cells (NFATc1) in the regulation of transcriptional programs throughout PDAC progression. Genome-wide transcriptome analysis and functional studies performed in primary PDAC cells and transgenic mice linked nuclear NFATc1 expression with pro-proliferative and anti-apoptotic gene signatures. Consistently, NFATc1 depletion resulted in downregulation of target genes associated with poor PDAC outcome and delayed pancreatic carcinogenesis in vivo. In contrast to previous reports and consistent with a concept of retained tumor suppressive TGFβ activity, even in established PDAC, TGFβ treatment reduced PDAC cell proliferation and promoted apoptosis even in the presence of oncogenic NFATc1. However, combined TGFβ treatment and NFATc1 depletion resulted in a tremendous abrogation of tumor-promoting gene signatures and functions. Chromatin studies implied that TGFβ-dependent regulators compete with NFATc1 for the transcriptional control of jointly regulated target genes associated with an unfavorable PDAC prognosis. Together, our findings suggest opposing consequences of TGFβ and NFATc1 activity in the regulation of pro-tumorigenic transcription programs in PDAC and emphasize the strong context-dependency of key transcription programs in the progression of this devastating disease.

Pancreatic ductal adenocarcinoma (PDAC) constitutes the most common malignancy of the pancreas. With a 5-year survival rate of below 10% and a median survival of less than 12 months following diagnosis, PDAC remains a major biomedical challenge. Due to the lack of early symptoms patients are usually diagnosed with locally advanced or metastatic disease where surgical removal of the tumour is no longer feasible. Despite some recent developments in medical oncology, response to chemotherapeutic regimens such as nab-paclitaxel and FOLFIRINOX is limited and accompanied by side effects such as nausea, neutropenia, neuropathy and infectious complications.1 Histologically, the majority of PDAC cases are characterised by tubular adenocarcinoma of the ductal glands embedded in a pronounced tumour microenvironment (TME) composed of acellular components such as collagen, hyaluronic acid, fibronectin and abundant matricellular proteins. Moreover, inflammatory cells such as tumour-associated macrophages, tumour-associated neutrophils, regulatory T cells, cancer-associated fibroblasts and neural cells accumulate around neoplastic cells and actively contribute to TME formation and tumour-stroma crosstalk.2 Notably, histopathological features of PDAC have not yet been used to select therapeutic strategies. However, increasing evidence from other tumour entities such as breast, melanoma, lung or colon cancer suggest that molecular characteristics can vastly differ in microscopically indistinguishable cancers. With the advent of high-throughput sequencing technologies such as whole-genome profiling and transcriptome profiling, molecular taxonomy of cancers has become …