Colorectal cancer (CRC) is the third most prevalent cancer globally, just behind breast and lung cancers. According to the International Agency for Research on Cancer (IARC), a subsidiary of the World Health Organization, there were 1.93 million newly diagnosed cases and 916,000 deaths of colorectal cancer worldwide in 2020[1]. However, the treatment options for CRC are often expensive and have limited efficacy, causing severe adverse effects among patients.

Figure 1. Estimated number of new cases in 2020, colorectum, both sexes, all ages [1]

In China, despite rapid economic development, the prevention and control of cancer haven’t progressed at the same speed. The numbers of confirmed cases and deaths of colorectal cancer have been increasing, and the onset age is on average 10 years earlier than that in Western countries. In 2016, China reported 400,000 confirmed cases of colorectal cancer, ranking the second among all cancers, and 190,000 deaths, ranking the fifth among all cancers[2]. These statistics highlight the urgent need for improved treatment options for colorectal cancer in China.

Based on the information from various sources, we believe that the treatment of colorectal cancer is in an urgent need.

Figure 2. Estimated numbers of new cancer cases and incidence rates, overall, by sex and cancer type in China, 2016. [2]

Figure 3. Estimated cancer deaths and mortality rates, overall, by sex and cancer type in China, 2016.[2]

Intestinal flora alteration, particularly with the presence of Fusobacterium nucleatum (Fn), is a major contributor to CRC metastasis. Fn, an oral anaerobic gram-negative bacillus, colonizes the colon tissues through diet and influences CRC development and metastasis through various mechanisms. Fn influences CRC by immune responses, virulence factors, microRNAs, metabolites, and DNA damage, promoting CRC development and spread. [3]

Through our research, we discovered that understanding Fn’s role in CRC metastasis will provides insights for developing targeted therapies and interventions.

Figure 4. Mechanisms through which Fn can promote CRC[3]

It has been reported that Fn is a key pathogenic factor and microbial biomarker in CRC[4] and clearing Fn by antibiotics can regress CRC[5]. To further investigate the relationship between CRC and Fn, we conducted bioinformatics analysis. We found that Fn was enriched in CRC patients compared to healthy individuals, and the expression of CRC genes correlated with Fn. Furthermore, we discovered that patients with Fn-mediated CRC exhibited a shorter survival period and poor prognosis.

Hence, we recognize the significance of targeting and eliminating both Fn and CRC cells in our project. To achieve this, we have conceived the idea of engineering a bacterium capable of simultaneously eradicating both enemies. That is BI-BYE: A solution of Engineering Probiotics for Colorectal Cancer. Scientists have struggled for cancer therapies for deacades, and we hope this new therapy, when fully developed, will cure Fn-mediated CRC, reduce patients’ pain from chemotherapy and relieve their families.

Our solution

Figure 5. Proposed implementation of BI-BYE.[3]
Delivery, Dual-targeting, TME Sensing, Dual-killing, Suiside

To improve the therapeutic effect of colorectal cancer and reduce potential damage to other tissues, the engineered BI-BYE will be free-dried and filled into colon soluble gelatin hollow capsules, so that the BL will only be released in the colorectal area. Two types of Fishing Rod Proteins (FRPs) displayed on the bacteria’s surface will target Fn or CRC cells, that’s what we called dual-targeting. Since BL also has the ability to target tumor, the accuracy of targeting will be improved. Once BI-BYE is located in the tumor microenvironment (TME), the expression and secretion of Cytotoxic Proteins will be initiated by a hypoxia-responsive module. One characteristic of TME is hypoxia, so the module can only work in TME. The Cytotoxic Proteins are capable of targeting and killing both Fn and CRC cells, thus achieving dual-killing. BI-BYE can colonize the colon and function for an extended period. Additionally, to ensure the safety of the engineered bacteria, we have designed two suicide systems to prevent harm from both humans and the environment.

FRPs and Cytotoxic Proteins are the cores of our projects, th for more information, please read following chapters: