AI-Powered cellular morphometric biomarkers discovered in needle biopsy of prostatic cancer predict neoadjuvant androgen deprivation therapy response and prognosis: an international multicenter retrospective study.

Unlabelled: It is imperative to identify patients with prostate cancer (PCa) who will benefit from androgen receptor signaling inhibitors that can impact quality of life upon prolonged use. Using our extensively-validated artificial-intelligence technique: cellular morphometric biomarker via machine learning (CMB-ML), we identified 13 CMBs from whole slide images of needle biopsies from the trial specimens ( NCT02430480 , n=37) that accurately predicted response to neoadjuvant androgen deprivation therapy (NADT) (AUC: 0.980).

Monitoring TGFβ signaling in irradiated tumors.

Transforming growth factor β (TGFβ) is exquisitely regulated under physiological conditions but its activity is highly dysregulated in cancer. All cells make TGFβ and have receptors for the ligand, which is sequestered in the extracellular matrix in a latent form. Ionizing radiation elicits rapid release of TGFβ from these stores, so-called activation, over a wide range of doses and exposures, including low dose (<1Gy) whole-body irradiation, creating an extraordinarily potent signal in the irradiated tissue or tumor.

Updates on radiotherapy-immunotherapy combinations: Proceedings of 6 annual ImmunoRad conference.

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels.

Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy.

Even though the number of agents that inhibit TGFβ being tested in patients with cancer has grown substantially, clinical benefit from TGFβ inhibition has not yet been achieved. The myriad mechanisms in which TGFβ is protumorigenic may be a key obstacle to its effective deployment; cancer cells frequently employ TGFβ-regulated programs that engender plasticity, enable a permissive tumor microenvironment, and profoundly suppress immune recognition, which is the target of most current early-phase trials of TGFβ inhibitors. Here we discuss the implications of a less well-recognized aspect of TGFβ biology regulating DNA repair that mediates responses to radiation and chemotherapy.

SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal.

Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown.

The radiobiology of TGFβ.

Ionizing radiation is a pillar of cancer therapy that is deployed in more than half of all malignancies. The therapeutic effect of radiation is attributed to induction of DNA damage that kills cancers cells, but radiation also affects signaling that alters the composition of the tumor microenvironment by activating transforming growth factor β (TGFβ). TGFβ is a ubiquitously expressed cytokine that acts as biological lynchpin to orchestrate phenotypes, the stroma, and immunity in normal tissue; these activities are subverted in cancer to promote malignancy, a permissive tumor microenvironment and immune evasion.

Validation of Anticorrelated TGFβ Signaling and Alternative End-Joining DNA Repair Signatures that Predict Response to Genotoxic Cancer Therapy.

Purpose: Loss of TGFβ signaling increases error-prone alternative end-joining (alt-EJ) DNA repair. We previously translated this mechanistic relationship as TGFβ and alt-EJ gene expression signatures, which we showed are anticorrelated across cancer types. A score representing anticorrelation, βAlt, predicts patient outcome in response to genotoxic therapy.

Mammary Tumor-Derived Transplants as Breast Cancer Models to Evaluate Tumor-Immune Interactions and Therapeutic Responses.

In breast cancer, the type and distribution of infiltrating immune cells are associated with clinical outcome. Moreover, cancers with abundant tumor-infiltrating lymphocytes (TIL) are more likely to respond to immunotherapy, whereas those in which CD8 T cells are completely absent (deserts) or excluded are less likely to respond. Detailed understanding of this biology is limited by a lack of preclinical breast cancer models that recapitulate TIL distributions and their associated biology.

Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment.

Transforming growth factor-β (TGF-β) and programmed death ligand 1 (PD-L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF-β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-to-mesenchymal transition, and angiogenesis. Meanwhile, PD-L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME.

Exploiting Canonical TGFβ Signaling in Cancer Treatment.

TGFβ is a pleiotropic cytokine that plays critical roles to define cancer cell phenotypes, construct the tumor microenvironment, and suppress antitumor immune responses. As such, TGFβ is a lynchpin for integrating cancer cell intrinsic pathways and communication among host cells in the tumor and beyond that together affect responses to genotoxic, targeted, and immune therapy. Despite decades of preclinical and clinical studies, evidence of clinical benefit from targeting TGFβ in cancer remains elusive.

Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants.

Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings.

Loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types.

Among the pleotropic roles of transforming growth factor-β (TGFβ) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGFβ signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a "backup" pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown.

Inflammation Mediates the Development of Aggressive Breast Cancer Following Radiotherapy.

Purpose: Women treated with radiotherapy before 30 years of age have increased risk of developing breast cancer at an early age. Here, we sought to investigate mechanisms by which radiation promotes aggressive cancer.

Experimental Design: The tumor microenvironment (TME) of breast cancers arising in women treated with radiotherapy for Hodgkin lymphoma was compared with that of sporadic breast cancers.

Positron Emission Tomography Imaging of Functional Transforming Growth Factor β (TGFβ) Activity and Benefit of TGFβ Inhibition in Irradiated Intracranial Tumors.

Purpose: Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed.

Misrepair in Context: TGFβ Regulation of DNA Repair.

Repair of DNA damage protects genomic integrity, which is key to tissue functional integrity. In cancer, the type and fidelity of DNA damage response is the fundamental basis for clinical response to cytotoxic therapy. Here we consider the contribution of transforming growth factor-beta (TGFβ), a ubiquitous, pleotropic cytokine that is abundant in the tumor microenvironment, to therapeutic response.

Autocrine TGFβ Is a Survival Factor for Monocytes and Drives Immunosuppressive Lineage Commitment.

Transforming growth factor β (TGFβ) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between and genes expressed by myeloid cells, but not granulocytes, in The Cancer Genome Atlas lung adenocarcinoma data, in which high expression was associated with poor survival. To determine whether TGFβ affected cell fate decisions and lineage commitment, we studied primary cultures of CD14 monocytes isolated from peripheral blood of healthy donors.