Biology subjects

Morotti, M.

Publications and source records attributed to Morotti, M..

5 recordsLinked to original sources

bioRxiv2024

Myeloid cell networks determine reinstatement of original immune environments in recurrent ovarian cancer

Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled 170 patient-matched primary-recurrent OC samples from 69 patients of two independent cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant evolution after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic patterns of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches and immunostimulatory tumour-associated macrophages (TAMs). Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the crosstalk between dissimilar myeloid cells and TILs, which is BRCA-dependent.

immunology↗

bioRxiv2022

Tumor Microenvironment Cellular Crosstalk Predicts Response to Adoptive TIL Therapy in Melanoma

Adoptive cell therapy (ACT) using ex vivo expanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+ TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+ T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials. One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+ TIL-myeloid cell networks

immunology↗

bioRxiv2022

Single Cell Transcriptomics identifies a WNT7A-FZD5 Signaling Axis that maintains Fallopian Tube Stem Cells in Patient-derived Organoids

Despite its significance to reproduction, fertility, sexually transmitted infections and various pathologies, the fallopian tube (FT) is relatively understudied. Strong evidence points to the FT as the tissue-of-origin of high grade serous ovarian cancer (HGSOC), the most fatal gynaecological malignancy. HGSOC precursor lesions arise specifically in the distal FT (fimbria) which is reported to be enriched in stem-like cells. Investigation of the role of FT stem cells in health and disease has been hampered by a lack of characterization of FT stem cells and lack of models that recapitulate stem cell renewal and differentiation in vitro. Using optimized organoid culture conditions to address these limitations, we found that FT stem cell renewal is highly dependent on WNT/{beta}-catenin signaling and engineered endogenous WNT/{beta}-catenin signaling reporter organoids to biomark, isolate and characterize putative FT stem cells. Using functional approaches as well as bulk and single cell transcriptomic analyses, we show that an endogenous hormonally-regulated WNT7A-FZD5 signaling axis is critical for self-renewal of human FT stem cells, and that WNT/{beta}-catenin pathway-activated FT cells form a distinct transcriptomic cluster of cells enriched in ECM remodelling and integrin signaling pathways. In addition, we find that the WNT7A-FZD5 signaling axis is dispensable for mouse oviduct regeneration. Overall, we provide a deep characterization of FT stem cells and their molecular requirements for self-renewal, paving the way for mechanistic work investigating the role of stem cells in FT health and disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/502319v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@124d8a0org.highwire.dtl.DTLVardef@9f92borg.highwire.dtl.DTLVardef@c57b33org.highwire.dtl.DTLVardef@11b5bec_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH can be accurately measured when informed by the molecular signatures of the normal cells of origin. We surveyed the transcriptomes of [~] 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of [~]1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.\n\nHighlightsO_LIThe projection of FTE subtypes refines the molecular classification of serous OC\nC_LIO_LIComprehensive single-cell profiling of FTE cells identifies 6 molecular subtypes\nC_LIO_LISubstantial non-genetic heterogeneity of HGSOC identified in 1700 tumors\nC_LIO_LIA mesenchymal-high HGSOC subtype is robustly correlated with poor prognosis\nC_LI

cancer biology↗

bioRxiv2018

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine-resistance in breast cancer

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor- (ER) positive breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer and it is regulated by HIF1 both in-vitro and in-vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ER but it became predominantly a HIF-1-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1 and ER overlap in SNAT2s cis-regulatory elements. In addition, the downregulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia.\n\nOverexpression of SNAT2 in-vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ER inhibition, in hypoxia, or when glutamine levels were low. SNAT2 upregulation in-vivo caused complete resistance to anti-estrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlate with HIF-1 and worse outcome in patients given anti-estrogen therapy. Our findings show a switch in regulation of SNAT2 between ER and HIF-1, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.

cancer biology↗