Biology subjects

Lennerz, J. K.

Publications and source records attributed to Lennerz, J. K..

4 recordsLinked to original sources

bioRxiv2024

A unique interplay of access and selection shapes peritoneal metastasis evolution in colorectal cancer

Whether metastasis in humans can be accomplished by most primary tumor cells or requires the evolution of a specialized trait remains an open question. To evaluate whether metastases are founded by non-random subsets of primary tumor lineages requires extensive, difficult-to-implement sampling. We have realized an unusually dense multi-region sampling scheme in a cohort of 26 colorectal cancer patients with peritoneal metastases, reconstructing the evolutionary history of on average 28.8 tissue samples per patient with a microsatellite-based fingerprinting assay. To assess metastatic randomness, we evaluate inter- and intra-metastatic heterogeneity relative to the primary tumor and find that peritoneal metastases are more heterogeneous than liver metastases but less diverse than locoregional metastases. Metachronous peritoneal metastases exposed to systemic chemotherapy show significantly higher inter-lesion diversity than synchronous, untreated metastases. Projection of peritoneal metastasis origins onto a spatial map of the primary tumor reveals that they often originate at the deep-invading edge, in contrast to liver and lymph node metastases which exhibit no such preference. Furthermore, peritoneal metastases typically do not share a common subclonal origin with distant metastases in more remote organs. Synthesizing these insights into an evolutionary portrait of peritoneal metastases, we conclude that the peritoneal-metastatic process imposes milder selective pressures onto disseminating cancer cells than the liver-metastatic process. Peritoneal metastases unique evolutionary features have potential implications for staging and treatment.

genetics↗

bioRxiv2023

Thermo-Responsive Polymers Targeting Inflammation in Murine Colitis

Targeting the site of inflammation is an ideal approach for treating inflammatory bowel disease (IBD). Inflammation targeting enables maximal drug-on-target effects while minimizing off-target side effects. Negatively charged drug carriers have been shown to facilitate drug delivery to inflamed colon mucosa after local administration. To modulate the negative charges and integrate responsiveness to stimuli, here we describe thermo-responsive, inflammation-targeting (TRIT) hydrogels based on functionalized poly(N-isopropylacrylamide-co-methacrylic acid) (PNIPAM-MAA). We show that both chemical modification types and polymer molecular weights affect the resultant microgels adhesion to the inflamed colon in dextran sulfate sodium (DSS)-induced murine colitis in vivo. Further, we quantified the correlations between microgels adhesion and colitis severity for individual mice, demonstrating that the microgels adhesion correlated directly with weight loss percentage in DSS-treated mice. By exploiting charge-mediated interaction and thermo-responsiveness, TRIT hydrogels represent a promising strategy to target inflamed colon mucosa as a drug delivery platform for colonic IBD treatment. TeaserThis study developed thermo-responsive, inflammation-targeting (TRIT) hydrogels that harness charge-mediated interaction and sol-to-gel transition to target inflamed colon mucosa as a new approach for treating inflammatory bowel disease.

bioengineering↗

bioRxiv2023

Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia

Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including touch, temperature, and pain to the central nervous system. Recent advances in single-cell RNA-sequencing (scRNA-seq) have provided new insights into the diversity of sensory ganglia cell types in rodents, non-human primates, and humans, but it remains difficult to compare transcriptomically defined cell types across studies and species. Here, we built cross-species harmonized atlases of DRG and TG cell types that describe 18 neuronal and 11 non-neuronal cell types across 6 species and 19 studies. We then demonstrate the utility of this harmonized reference atlas by using it to annotate newly profiled DRG nuclei/cells from both human and the highly regenerative axolotl. We observe that the transcriptomic profiles of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The new resources and data presented here can guide future studies in comparative transcriptomics, simplify cell type nomenclature differences across studies, and help prioritize targets for future pain therapy development.

neuroscience↗

bioRxiv2020

Tumor-Immune Partitioning and Clustering (TIPC) algorithm reveals distinct signatures of tumor-immune cell interactions within the tumor microenvironment

Growing evidence supports the importance of understanding tumor-immune spatial relationship in the tumor microenvironment in order to achieve precision cancer therapy. However, existing methods, based on oversimplistic cell-to-cell proximity, are largely confounded by immune cell density and are ineffective in capturing tumor-immune spatial patterns. Here we developed a novel computational algorithm, termed Tumor-Immune Partitioning and Clustering (TIPC), to offer an effective solution for spatially informed tumor subtyping. Our method could measure the extent of immune cell partitioning between tumor epithelial and stromal areas as well as the degree of immune cell clustering. Using a U.S. nation-wide colorectal cancer database, we showed that TIPC could determine tumor subtypes with unique tumor-immune spatial patterns that were significantly associated with patient survival and key tumor molecular features. We also demonstrated that TIPC was robust to parameter settings and readily applicable to different immune cell types. The capability of TIPC in delineating clinically relevant patient subtypes that encapsulate tumor-immune spatial relationship, immune density, and tumor morphology is expected to shed light on underlying immune mechanisms. Hence, TIPC can be a useful bioinformatics tool for effective characterization of the spatial composition of the tumor-immune microenvironment to inform precision immunotherapy.

cancer biology↗