Biology subjects

Campos, T.

Publications and source records attributed to Campos, T..

4 recordsLinked to original sources

bioRxiv2026

Myc inhibition triggers GM-CSF-driven regression of pancreatic tumours

The complex aetiology of pancreatic ductal adenocarcinoma (PDAC), together with its desmoplastic and hypoxic microenvironment, hinders effective treatment and contributes to its rapid lethality1. Using a reversibly switchable genetic mouse model that closely recapitulates human PDAC phenotype progression, we previously showed that selective deactivation of oncogenic Myc in PDAC epithelial cells triggers rapid disassembly of advanced PDACs2, both tumor cells and their associated immune microenvironment. Here, leveraging spatiotemporal genomics and multiplex immune profiling we determine the mechanism underpinning this regression programme and identify granulocyte-macrophage colony-stimulating factor (GM-CSF) as its key instructive cytokine, transiently released by pancreatic ductal epithelial cells rapidly following Myc inactivation, that initiates tumour regression. We further demonstrate that type 1 conventional dendritic cells (cDC1s) act as critical effectors in Myc-OFF GM-CSF-driven tumour regression. Both antibody-mediated blockade of GM-CSF and genetic ablation of cDC1s via Batf3 knockout bone marrow transplantation prevent PDAC regression. Conversely, transient systemic administration of recombinant GM-CSF to PDAC-bearing mice promotes rapid cDC1 infiltration and induces marked tumour regression in the sustained presence of Myc activity. Together, these findings reveal that PDAC regression induced by Myc de-activation is mediated by a latent morphogenic programme that is initiated by transient release of GM-CSF from tumour cells. This regression programme is rapid, tissue-specific, involves both neoplastic cells and attendant desmoplastic stroma, is reliant on innate immunity and provides a novel framework for therapeutic intervention in PDAC.

cancer biology↗

bioRxiv2026

Targeting Myc activates a tissue-specific tumour resolution programme

Neoplastic transformation parallels hallmark cellular programs of tissue regeneration and wound repair1,2. However, the mechanisms driving tumour regression upon oncogenic driver inhibition--and why it often fails--remain poorly understood3-7. Oncogenic KRas mutations and Myc deregulation, two archetypal cancer drivers, frequently occur and cooperate to promote aggressive lung adenocarcinoma (LUAD)8-12. To investigate the mechanistic consequences of targeting Myc in LUAD, we applied spatiotemporally controlled genetic and functional perturbations in a reversible KRas/Myc-driven mouse model, integrated with RNA sequencing and immune protein profiling of tumours and their microenvironment. Acute oncogenic Myc inactivation in epithelial tumour cells elicits a localised regenerative immune response crucially dependent on rapid, transient release of the alarmin cytokine interleukin-33 (IL-33) by alveolar type 2 tumour cells. As a sentinel signal for Myc loss, IL-33 signalling reverses tumour immunosuppression and neoangiogenesis, critically recruits eosinophils, and promotes neoplastic cell elimination, driving regression beyond mere growth arrest. Notably, brief systemic recombinant IL-33 administration to mice with KRas/Myc-driven LUAD induces robust eosinophil influx and near-complete tumour resolution. Together, these findings demonstrate that blocking Myc activates an innate, tissue-intrinsic immune programme rooted in resolution of wound repair and capable of driving regression when activated in a tumour. This opens the possibility of treating cancer not only by blocking mitogenic oncogenic drivers but also by pro-actively triggering pro-resolution pathways.

cancer biology↗

bioRxiv2025

Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8+ T cells underlies distinct functional potential

Persistent antigen stimulation promotes differentiation of exhausted CD8+ T (TEX) cells. TEX cells are distinct from circulating memory T (TCIRCM) cells but share many features with tissue-resident memory (TRM) cells established following infection resolution. CD8+ T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional TRM or TEX cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident TEX (TR-TEX) cells that are ontologically and functionally distinct from TRM cells generated after antigen clearance. TR-TEX phenotypically resembled TRM cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although TEX progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional TRM cells after antigen withdrawal. Conversely, TRM cells were able to differentiate into TEX cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-TEX cells with patient responses to immune checkpoint blockade, and only TR-TEX but not TRM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-TEX and TRM cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.

immunology↗

bioRxiv2019

Myc instructs and maintains pancreatic adenocarcinoma phenotype

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its dismal prognosis and its signature fibroinflammatory phenotype. We show that activation of Myc in PanIN epithelial cells is alone sufficient to instruct and maintain immediate transition of indolent PanINs to PDACs phenotypically identical to the spontaneous human disease. Myc does this by inducing a distinct, tissue-specific ensemble of instructive signals that, together, coordinate changes in multiple, stromal and inflammatory cell types to generate the signature PDAC stroma. We also demonstrate that the Myc PDAC switch is completely reversible and that Myc deactivation immediately triggers meticulous disassembly of both PDAC tumor and stroma. Hence, both the formation and deconstruction of the complex PDAC phenotype may be mediated by a single, reversible molecular switch. SIGNIFICANCEPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and lacks effective therapies. We show that Myc is a single molecular switch that directly and immediately instructs transition from indolent KRasG12D-induced PanIN to the characteristic complex, multi-cell-type fibroinflammatory and immune-cold PDAC phenotype through the release of a distinct, tissuespecific set of instructive signals. The same combination of KRasG12D and Myc drives a very different phenotype in lung, indicating that the principal phenotypes of adenocarcinomas are dictated by tissue of origin not specific oncogenes. We also show that the Myc switch is immediately and completely reversible: blocking Myc function triggers meticulous disassembly of the entire PDAC tumor-stromal edifice demonstrating that phenotypic complexity is not a barrier to effective treatment of cancers.

cancer biology↗