Aiello, M. | Search bioRxiv

bioRxiv2026

Spatial Logic Reconciles Gene-signature Methods in Triple Negative Breast Cancer

Triple-Negative Breast Cancer (TNBC) presents a significant clinical challenge due to its heterogeneity and lack of targeted treatment options, with chemotherapy and immunotherapy combinations currently serving as the main therapeutic strategy. Efforts to address TNBC heterogeneity have largely focused on classifying intrinsic cancer subtypes based on differential tumor mRNA expression, a strategy that has proven effective in hormone receptor-positive breast cancers but has yet to yield a clinically useful predictor of survival or treatment response in TNBC. We hypothesize that both the intrinsic characteristics of TNBC and the surrounding immune microenvironment influence treatment outcomes and that immune cell infiltration affects TNBC subtype classification and response variability. To explore this hypothesis, we compared the predictive and prognostic capabilities of cancer subtype-based (TNBC-type) gene signatures and immune cell deconvolution methods (CIBERSORT) within the same TNBC datasets. We found that immune cell abundance outperformed TNBC subtype-signatures and multicellular immune cell aggregates showed the highest performance of all. More specifically, aggregate immune cells associated with tertiary lymphoid structures and tumor associated macrophages/monocytes demonstrated statistically significant predictive value. These findings were confirmed in an independent cohort of 67 TNBC patients treated with neoadjuvant chemotherapy. Further, single-cell RNA sequencing analysis revealed that the predictive power of cancer-subtype could be partially explained by immune- and stromal features. Examination of single-cell resolution spatial transcriptomic data confirmed presence of TLS-like, TAM- and cancer-stromal niches within TNBC biopsy samples that were associated with treatment response. Overall, our results highlight that immune cell aggregates, which capture the spatial organization of the TME, outperform cell-type specific gene signatures in predicting TNBC outcomes. Our novel approach provides a robust framework for interpreting spatial relationships in bulk RNA-seq data, offering a pathway for reconciling past data with current advancements in spatial profiling technologies. This work paves the way for future studies to leverage the multi-cellular complexity of TNBC, enhancing diagnostic precision and facilitating the development of therapies that strategically modulate the tumor microenvironment for improved anti-cancer responses.

cancer biology↗

bioRxiv2023

The impact of Subclinical Psychotic Symptoms on Delay and Effort discounting: insights from behavioral, computational, and electrophysiological methods

BackgroundThe ability to value rewards is crucial for adaptive behavior and is influenced by the time and effort required to obtain them. Impairments in these computations have been observed in patients with schizophrenia and may be present in individuals with subclinical psychotic symptoms (PS). MethodsIn this study, we employed delay and effort-discounting tasks with food rewards in thirty-nine participants divided into high and low levels of PS. We investigated the underlying mechanisms of effort-discounting through computational modelling of dopamine prefrontal and subcortical circuits and the electrophysiological biomarker of both delay and effort-discounting alterations through resting-state frontal alpha asymmetry (FAA). ResultsResults revealed greater delay discounting in the High PS group compared to the Low PS group but no differences in the effort discounting task. However, in this task, the same levels of estimated dopamine release were associated with a lower willingness to exert effort for high-calorie food rewards in High PS participants compared to Low PS participants. Although there were no significant differences in FAA between the High PS and Low PS groups, FAA was significantly associated with the severity of participants negative symptoms. ConclusionsOur study suggests that the dysfunction in temporal and effort cost computations, seen in patients with schizophrenia, may be present in individuals with subclinical PS. These findings provide valuable insight into the early vulnerability markers (behavioral, computational, and electrophysiological) for psychosis, which may aid in the development of preventive interventions.

neuroscience↗